This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Cancer is a disease rooted in the disregulation of protein-protein interactions;these comprise the underlying mechanisms for cell proliferation, differentiation, and death. Despite intense interest and considerable effort via high-throughput screening (HTS), there are few examples of small-molecules that directly inhibit protein-protein interactions. This suggests either that most protein interaction surfaces are not druggable targets, or else that current HTS libraries are not well-suited for this task. A recent survey identified the few examples of protein structures that have been solved both in complex with a biological protein partner and also in complex with a small molecule inhibitor [unreadable]a list that includes important oncoproteins such as Bcl-xL. Comparison of the unbound protein structure to the equivalent structure in complex with a small molecule shows that while binding is not associated with a large conformational change, the concave pocket on the protein surface in which the small molecule binds is typically absent in the apo structure. My lab is currently focused on using computer simulations to predict the holo conformation of a protein (small-molecule bound) from the apo (unbound) conformation, assuming no knowledge of the small molecule's identity. In this COBRE CCET application, we propose to use map the ensemble of possible pocket shapes that can occur on the protein surface for each member of the Bcl-2 family. Together with the Medicinal Chemistry Laboratory, we will use this "pocket shape library" to prepare a targeted library of complementary small-molecules. In conjunction with the High Throughput Screening Laboratory, we will then screen this library for in vitro inhibition of the known protein-protein interaction and for in vivo activity. Since our library will derive from pocket shapes of the target protein, we expect that our method will be particularly well poised to identify inhibitors with new chemotypes ("scaffold hopping"). We therefore anticipate our novel approach will lead to identification of new inhibitory compounds for this family of well-validated targets.